Nicotinic acetylcholine receptors (nAChRs) are essential to behaviors as basic as breathing and as mysterious as motivation, memory and mood. The overall goal of the NS 022061 program is elucidate the role of central cholinoceptive circuits that are affected in neuropsychiatric, neurodegenerative and addictive disorders, with the long range goal of accelerating the development of novel therapeutics. Whereas prior studies have been limited to probing the role of nicotinic acetylcholine receptors (nAChRs) in cholinoceptive circuits by application of agonists or antagonists, we are now armed with multiple genetic, optogenetic and new molecular tools that permit dissection of how direct activation of endogenous cholinergic neurons regulates cortico-limbic excitability. With these new approaches in hand, we can test how cortico-limbic circuits are altered by peri-natal vs. adolescent exposure to nicotine, the world's most common drug of abuse. PUBLIC HEALTH RELEVANCE: Despite the crucial role of acetylcholine throughout life and the fact that nicotine self-administration is the single greatest cause of preventable death in the world, basic aspect of cholinergic signaling remain mysterious. The goal of this project is to determine how acetylcholine modulates cortico-limbic circuits that are pertinent to motivated behaviors, by modulating the activity of brain regions conveying information related to emotional context, sensory cues, executive function and novelty vs. prior experience.